Gr/gr deletions on Y-chromosome correlate with male infertility: an original study, meta-analyses, and trial sequential analyses

Abstract

We analyzed the AZFc region of the Y-chromosome for complete (b2/b4) and distinct partial deletions (gr/gr, b1/b3, b2/b3) in 822 infertile and 225 proven fertile men. We observed complete AZFc deletions in 0.97% and partial deletions in 6.20% of the cases. Among partial deletions, the frequency of gr/gr deletions was the highest (5.84%). The comparison of partial deletion data between cases and controls suggested a significant association of the gr/gr deletions with infertility (P = 0.0004); however, the other partial deletions did not correlate with infertility. In cohort analysis, men with gr/gr deletions had a relatively poor sperm count (54.20 ± 57.45 million/ml) in comparison to those without deletions (72.49 ± 60.06), though the difference was not statistically significant (p = 0.071). Meta-analysis also suggested that gr/gr deletions are significantly associated with male infertility risk (OR = 1.821, 95% CI = 1.39-2.37, p = 0.000). We also performed trial sequential analyses that strengthened the evidence for an overall significant association of gr/gr deletions with the risk of male infertility. Another meta-analysis suggested a significant association of the gr/gr deletions with low sperm count. In conclusion, the gr/gr deletions show a strong correlation with male infertility risk and low sperm count, particularly in the Caucasian populations.

Figure 1. Distribution and the effect of Y-partial deletions:

(A) Pie chart showing the frequencies (%) of the AZFc partial deletions in the cases (n = 822), (B) Cohort analysis showing sperm count between groups with and without gr/gr deletions.

Figure 2. Retrieval of studies for meta-analysis: Flow diagram showing stepwise screening of the studies for inclusion in the meta-analysis.

Figure 3. Forest plot (overall):

upper panel shows the pooled estimate of all studies; lower panel shows the cumulative statistics.

Figure 4. Forest plot (sub-group):

upper panel shows pooled estimate on the sub-groups based on ethnicity; lower panel shows the pooled estimate on the sub-groups based on the geographic region.

Figure 5. Meta-analysis comparing sperm count between gr/gr deleted and non-deleted groups:

(A) overall meta-analysis, (B) sensitivity analysis showing the sensitive study (Choi et al., 2012), and C) Pooled estimate after removal of the sensitive study.

Figure 6. Trial sequential analysis on all pooled studies, ethnicity-wise and geographic region-wise.